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This week's highlights

Biological Sciences

Many factors contribute to risk of alcohol abuse but their relative importance is difficult to quantify. Robert Whelan et al. constructed models of current and future adolescent binge drinking using data from the IMAGEN project, a study of risk-taking behaviour in over 2,000 teenagers recruited at age 14 from the United Kingdom, Ireland, France and Germany. A key finding is that personality factors are – surprisingly – not particularly useful predictors of future alcohol misuse. But neurodevelopmental immaturity, functional indicators in the brain, sexual experience and prenatal alcohol exposure are associated with current and future binge drinking.

Physical Sciences

Computers have evolved at a remarkable rate for fifty years, roughly in line with Gordon Moore's prediction that the number of transistors in a dense integrated circuit would double approximately every two years. The rate of 'Moore scaling' is slowing down and other physical limits are looming, but new technologies are on the way. In this Review Igor Markov takes a fresh look at the fundamental limits at various levels, from device to complete system levels. He argues that the study of the limits of fundamental limits to computation can lead to new insights for emerging technologies.

Earth & Environmental Sciences

Human populations living in the Tibetan uplands have had many thousands of years to adapt to life at a high altitude. The hypoxia pathway gene EPAS1 was shown previously to be associated with this adaptation. This study of the DNA sequence of the chromosomal region around EPAS1 in Tibetan and Han Chinese individuals has arrived at a surprising and important result. The unusual haplotype structure of the Tibetan individuals appears to have been due to the introduction of DNA from Denisovans, a Homo species or subspecies known from a few high-altitude fossil discoveries in Siberia.

Australia and New Zealand might be neighbours, but their programmes of research assessment are very different. Focusing on the tools and methods used to measure the quality and impact of science in Australia and New Zealand should inform similar debates throughout the scientific world.

The mammalian aryl hydrocarbon receptor (known to sense environmental pollutants) is shown to also have a role as a pattern recognition receptor in sensing bacterial virulence factors, resulting in an antibacterial response and activation of innate and natural defences.

Here, a long noncoding RNA, termed Mhrt, is identified in the loci of myosin heavy chain (Myh) genes in mice and shown to be capable of suppressing cardiomyopathy in the animals, as well as being repressed in diseased human hearts.

KRAS mutations are a driver event of pancreatic ductal adenocarcinoma; here, a subpopulation of dormant tumour cells, relying on oxidative phosphorylation for survival, is shown to be responsible for tumour relapse after treatment targeting the KRAS pathway.

A mutation in VRC01, a broadly neutralizing, HIV-1-specific antibody, confers enhanced binding to the neonatal Fc receptor, increasing the antibody half-life in the serum and localization in mucosal tissues, where it provides superior protection against rectal simian HIV-1 infection in macaques.

Notch signalling has a key role in the generation of haematopoietic stem cells (HSCs) during vertebrate development; here two adhesion molecules, Jam1a and Jam2a, are shown to be essential for the contact between precursors of HSCs and the somite during embryonic migration, and the Jam1a–Jam2a interaction is shown to be needed to transmit the Notch signal and produce HSCs.

A new somite compartment, called the endotome, that contributes to the formation of the embryonic dorsal aorta by providing endothelial progenitors is identified here; endotome-derived endothelial progenitors, whose formation is regulated by the activity of the meox1 gene, induce haematopoietic stem cell formation upon colonization of the nascent dorsal aorta.

The Piezo1 calcium-permeable channel is revealed to have a role in the vascular cellular response to shear stress; a mouse knockout reveals that this channel is also important for normal vascular development.

The CRISPR/Cas system is an RNA-guided bacterial protection system against foreign nucleic acids of bacterial and archaeal origin; here a high-resolution crystal structure of the CRIPSR RNA–Cas complex shows that the CRIPSR RNA plays an essential role not only in target recognition but also in complex assembly.

Articles and Letters

To investigate genomic diversity within tumours, a new type of whole-genome and exome single cell sequencing has been developed using G2/M nuclei; the technique was used to sequence single nuclei from an oestrogen-positive breast cancer and a triple-negative ductal carcinoma—aneuploidy rearrangements emerged as early events in tumour formation and then point mutations evolved gradually over time.

The COP9 signalosome (CSN) complex regulates cullin–RING E3 ubiquitin ligases—the largest class of ubiquitin ligase enzymes, which are involved in a multitude of regulatory processes; here, the crystal structure of the entire human CSN holoenzyme is presented.

The three-dimensional structure of intact human γ-secretase complex at 4.5 Å resolution is revealed by cryo-electron-microscopy single-particle analysis; the complex comprises a horseshoe-shaped transmembrane domain containing 19 transmembrane segments, and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the horseshoe.

Many factors have been proposed as contributors to risk of alcohol abuse, but quantifying their influence has been difficult; here a longitudinal study of a large sample of adolescents and machine learning are used to generate models of predictors of current and future alcohol abuse, assessing the relative contribution of many factors, including life history, individual personality differences, brain structure and genotype.

An association mapping study of type-2-diabetes-related quantitative traits in the Greenlandic population identified a common variant in TBC1D4 that increases plasma glucose levels and serum insulin levels after an oral glucose load and type 2 diabetes risk, with effect sizes several times larger than any previous findings of large-scale genome-wide association studies for these traits.

Admixture with other hominin species helped humans to adapt to high-altitude environments; the EPAS1 gene in Tibetan individuals has an unusual haplotype structure that probably resulted from introgression of DNA from Denisovan or Denisovan-related individuals into humans, and this haplotype is only found in Denisovans and Tibetans, and at low frequency among Han Chinese.

Haematopoietic stem cell (HSC) function is known to degrade with age; here, replication stress is shown to be a potent driver of the functional decline of HSCs during physiological ageing in mice due to decreased expression of mini-chromosome maintenance helicase components and reduced activity of the DNA replication machinery.

By characterizing a very large number of might-have-been evolutionary trajectories starting from a resurrected ancestral protein, the authors show that the evolution of an essential modern protein was contingent on extremely unlikely historical mutations.

Here, a long noncoding RNA, termed Mhrt, is identified in the loci of myosin heavy chain (Myh) genes in mice and shown to be capable of suppressing cardiomyopathy in the animals, as well as being repressed in diseased human hearts.

KRAS mutations are a driver event of pancreatic ductal adenocarcinoma; here, a subpopulation of dormant tumour cells, relying on oxidative phosphorylation for survival, is shown to be responsible for tumour relapse after treatment targeting the KRAS pathway.

The Piezo1 calcium-permeable channel is revealed to have a role in the vascular cellular response to shear stress; a mouse knockout reveals that this channel is also important for normal vascular development.

Articles and Letters

To investigate genomic diversity within tumours, a new type of whole-genome and exome single cell sequencing has been developed using G2/M nuclei; the technique was used to sequence single nuclei from an oestrogen-positive breast cancer and a triple-negative ductal carcinoma—aneuploidy rearrangements emerged as early events in tumour formation and then point mutations evolved gradually over time.

The three-dimensional structure of intact human γ-secretase complex at 4.5 Å resolution is revealed by cryo-electron-microscopy single-particle analysis; the complex comprises a horseshoe-shaped transmembrane domain containing 19 transmembrane segments, and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the horseshoe.

Many factors have been proposed as contributors to risk of alcohol abuse, but quantifying their influence has been difficult; here a longitudinal study of a large sample of adolescents and machine learning are used to generate models of predictors of current and future alcohol abuse, assessing the relative contribution of many factors, including life history, individual personality differences, brain structure and genotype.

An association mapping study of type-2-diabetes-related quantitative traits in the Greenlandic population identified a common variant in TBC1D4 that increases plasma glucose levels and serum insulin levels after an oral glucose load and type 2 diabetes risk, with effect sizes several times larger than any previous findings of large-scale genome-wide association studies for these traits.

RESEARCH

Latest Online

A model in which the stellar wind of the fast-moving red supergiant Betelgeuse is photoionized by radiation from external sources can explain the dense, almost static shell recently discovered around the star, and predicts both that debris from Betelgeuse’s eventual supernova explosion will violently collide with the shell and that other red supergiants should have similar, but much more massive, shells.

Articles and Letters

The contribution of solar-wind ions exchanging electrons with helium and hydrogen near the Sun is shown to be only about 40 per cent of the 1/4-keV X-ray flux observed in the Galactic plane; this supports the existence of a local ‘hot bubble’ filled with X-ray-emitting gas, accounting for the rest of the flux.

Modelling and observations of the kilometre-sized asteroid (29075) 1950 DA reveal it to be a ‘rubble pile’ that is rotating faster than is allowed by gravity and friction; cohesive forces such as those in lunar regolith are required to prevent it breaking up.

Metallic liquids of single elements have been successfully vitrified to their glassy states by achieving an ultrafast quenching rate in a new experimental design, of which the process has been monitored and studied by a combination of in situ transmission electron microscopy and atoms-to-continuum computer modelling.

Analysis of the Moon's topography reveals that when its largest basins are removed, the lunar shape is consistent with processes controlled by early Earth tides, and implies a reorientation of the Moon's principal shape axes.

Reviews and Perspectives

To evaluate the promise of potential computing technologies, this review examines a wide range of fundamental limits, such as to performance, power consumption, size and cost, from the device level to the system level.

The 2014 Iquique event was not the earthquake that had been expected to fill the regional seismic gap; given that significant sections of the northern Chile subduction zone have not ruptured in almost 150 years, it is likely that future megathrust earthquakes will occur south and potentially north of the 2014 Iquique sequence.

Articles and Letters

Analysis of the Moon's topography reveals that when its largest basins are removed, the lunar shape is consistent with processes controlled by early Earth tides, and implies a reorientation of the Moon's principal shape axes.

A model in which the stellar wind of the fast-moving red supergiant Betelgeuse is photoionized by radiation from external sources can explain the dense, almost static shell recently discovered around the star, and predicts both that debris from Betelgeuse’s eventual supernova explosion will violently collide with the shell and that other red supergiants should have similar, but much more massive, shells.

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